Ubiquitin proteasome-mediated protein degradation is an important process in maintaining cellular homeostasis through regulation of many important cellular processes, including differentiation, proliferation and apoptosis. Accordingly, aberrant protein degradation through this system underlies many diseases, including cancer. The mammalian target of rapamycin (mTOR), coupled with raptor and rictor to form mTOR complex 1 (mTORC1) and mTORC complex 2 (mTORC2), respectively, plays a critical role in the regulation of cell proliferation and survival. Hence, mTOR inhibitors including the conventional rapamycin and its analogues (rapalogs) and novel mTOR kinase inhibitors are either approved drugs for cancer therapy or being widely tested in clinical trials. We and other have suggested that mTOR, raptor and rictor can be degraded through a mechanism involving the E3 ubiquitin ligase FBXW7 (also called FBW7 or CDC4). However, the mechanisms underlying their degradation and the impact of degradation-mediated regulation of the mTOR axis on mTOR- targeted cancer therapy are largely unknown. In this proposal, we hypothesize that the key components in the mTOR complexes, rictor and raptor, are subjected to FBXW7-mediated and GSK3-dependent degradation. As a result, both mTORC1 and mTORC2 are regulated by the degradation mechanism. This hypothesis will be tested by accomplishing 3 aims: 1) to demonstrate FBXW7-mediated ubiquitination and proteasome degradation of raptor and rictor and its impact on the mTOR signaling;2) to determine the involvement of GSK3 in FBXW7-mediated degradation of rictor and raptor;and 3) to evaluate the impact of degradation regulation of the mTOR axis on mTOR-targeted cancer therapy. The objectives of this proposal are to understand the mechanisms through which raptor and rictor are degraded and to determine the impact of regulation of the degradation of these proteins on mTOR-targeted cancer therapy. PUBLIC HEALTH RELEVANCE: The objectives of the proposal are to understand the mechanisms through which raptor and rictor are degraded and to determine the impact of regulation of the degradation of these proteins on mTOR-targeted cancer therapy. Thus, this proposal not only helps us to understand the biology of mTOR regulation by degradation, but also has great translational significance that immediately impacts clinical treatment of cancer.